New regulators of nutrient-dependent growth control

In multicellular animals, growth rate needs to be balanced in all tissues, which sets the requirement for systemic hormonal control.

A key hormonal mechanism regulating growth in response to nutrition is the insulin-like pathway, which in flies is activated by insulin-like peptides and in vertebrates by insulin-like growth factors. We have used the power of Drosophila genetics to screen for new genes that control the secretion of insulin-like peptides (ILPs) in response to nutrition. These efforts led to the finding that an atypical MAP kinase ERK7 (also known as ERK8 and MAPK15) is a potent inhibitor of ILP secretion during nutrient starvation (Hasygar & Hietakangas, 2014). Consequently, ERK7 activity in the insulin producing cells inhibits animal growth. ERK7 expression is activated by starvation as well as in conditions of inhibited ribosome biogenesis. Our current work is addressing the role of ERK7 in nutrient-dependent regulation of growth and metabolism in other metabolically-relevant tissues.

It is well-established that nutrient-dependent growth control is coordinated by the Insulin/mTOR pathway. This pathway integrates information from hormonal signals as well as intracellular amino acid and energy levels to control anabolic reactions of the cell. A rate limiting process for cell growth is ribosome biogenesis. How ribosome biogenesis is regulated by mTOR complex 1 (mTORC1) and other growth-promoting pathways has remained insufficiently understood. We have discovered a new regulator involved in nutrient-dependent ribosome biogenesis, called PWP1 (Liu et al., 2017). PWP1 is a chromatin-binding protein conserved in eukaryotes, which promotes nutrient-responsive ribosomal RNA (rRNA) expression by RNA polymerase (Pol) I and III (Liu et al., 2017; Liu et al., 2018). Drosophila mutants lacking PWP1 show impaired growth, which is consistent with its role as a driver of ribosomal RNA expression. PWP1 is regulated at the levels of gene expression by the transcription factor Myc, which acts downstream of mTORC1 signaling. PWP1 is also phosphorylated in mTORC1-dependent manner and the PWP1 phosphorylation is needed for its localization in the nucleolus, the site of Pol I activity. Thus, PWP1 is a nutrient-responsive regulator of rRNA expression. Our current work focuses on the role of PWP1 in growth and metabolic control beyond the ribosome biogenesis.

Cancer cells depend on high protein biosynthetic activity and display highly elevated ribosome biogenesis. We have observed that PWP1 expression in elevated in human head and neck squamous cell carcinoma (HNSCC) tumours and the expression level of PWP1 positively correlates with the aggressiveness of the tumor (Liu et al., 2017). Knockdown of PWP1 in HNSCC tumour cells inhibits proliferation, demonstrating the functional importance of PWP1. Future studies will be needed to address the importance of PWP1 in a broader spectrum of cancer types.